Imidazo Compounds

ABSTRACT

The application relates to novel heterocyclic compounds of the general formula (I) and salts, preferably pharmaceutically acceptable salts, thereof in which R, R 1 , R 2 , Q, m and n have the meanings explained in detail in the description, a process for their preparation and the use of these compounds as medicaments, in particular as aldosterone synthase inhibitors.

FIELD OF THE INVENTION

The invention relates to novel heterocyclic compounds, processes forpreparing the compounds, pharmaceutical products containing them, andtheir use as active pharmaceutical ingredients, especially asaldosterone synthase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates firstly to compounds of the generalformula

in whichR is deuterium, halogen or hydrogen;R¹ is aryl-C₀-C₄-alkyl or heterocyclyl-C₀-C₄-alkyl, which radicals maybe substituted by 1-4 C₁-C₈ alkoxy, C₁-C₈ alkoxycarbonyl, C₁-C₈ alkyl,C₀-C₈ alkylcarbonyl, C₁-C₈ alkylsulphonyl, optionally substituted aryl,aryl-C₀-C₄ alkoxycarbonyl, cyano, halogen, optionally substitutedheterocyclyl, hydroxy, nitro, oxide, oxo, tri-C₁-C₄-alkylsilyl,trifluoromethoxy or trifluoromethyl;R² is a) deuterium, halogen, hydroxy, cyano or hydrogen; or

-   -   b) C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ alkoxy, C₁-C₄        alkoxycarbonyl-C₁-C₄ alkyl, C₁-C₈ alkyl, C₀-C₄ alkylcarbonyl,        aryl-C₀-C₄ alkyl, carboxy-C₀-C₄ alkyl, C₃-C₈ cycloalkyl or        heterocyclyl-C₀-C₄ alkyl, which radicals may be substituted by        1-4 C₁-C₈ alkoxy, C₁-C₈ alkoxycarbonyl, C₁-C₈ alkyl, C₀-C₈        alkylcarbonyl, C₁-C₈ alkylsulphonyl, optionally substituted        aryl, aryl-C₀-C₄ alkoxycarbonyl, cyano, halogen, optionally        substituted heterocyclyl, hydroxy, nitro, oxide, oxo, tri-C₁-C₄        alkylsilyl, trifluoromethoxy or trifluoromethyl;        Q is oxygen or sulphur;        m is a number 0, 1 or 2;        n is a number 0, 1 or 2;        where        m and n are not simultaneously 0;        and their salts, preferably their pharmaceutically acceptable        salts.

The term aryl stands for a mono-, bi- or tricyclic aromatic hydrocarboncomplying with the Hückel rule which generally comprises 6-14,preferably 6-10, carbon atoms and is for example phenyl, naphthyl, e.g.1- or 2-naphthyl or anthracenyl. Aryl having 6-10 carbon atoms, inparticular phenyl or 1- or 2-naphthyl, is preferred. The stated radicalsmay be unsubstituted or substituted one or more times, e.g. once ortwice, in which case the substituent may be in any position, e.g. in theo, m or p position of the phenyl radical or in the 3 or 4 position ofthe 1- or 2-naphthyl radical, and there may also be a plurality ofidentical or different substituents present. Examples of substituents onaryl radicals or the preferred phenyl or naphthyl radicals are: C₁-C₈alkoxy, C₁-C₈ alkoxycarbonyl, C₁-C₈ alkyl, C₀-C₈ alkylcarbonyl, C₁-C₈alkylsulphonyl, optionally substituted aryl, aryl-C₀-C₄ alkoxycarbonyl,cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro,tri-C₁-C₄ alkylsilyl, trifluoromethoxy or trifluoromethyl.

Aryl-C₀-C₄ alkyl is for example phenyl, naphthyl or benzyl.

The term heterocyclyl stands for a saturated, partially saturated orunsaturated, 4-8-membered, particularly preferably 5-membered,monocyclic ring system, for a saturated, partially saturated orunsaturated, 7-12-membered, particularly preferably 9-10-membered,bicyclic ring system and also for a partially saturated or unsaturated,9-12-membered tricyclic ring system which comprises an N, O or S atom inat least one of the rings, it being possible for an additional N, O or Satom to be present in one ring. Said radicals may be unsubstituted orsubstituted one or more times, e.g. once or twice, and there may also bea plurality of identical or different substituents present. Examples ofsubstituents on heterocyclyl radicals are: C₁-C₈ alkoxy, C₁-C₈alkoxycarbonyl, C₁-C₈ alkyl, C₀-C₈ alkylcarbonyl, C₁-C₈ alkylsulphonyl,optionally substituted aryl, aryl-C₀-C₄ alkoxycarbonyl, cyano, halogen,optionally substituted heterocyclyl, hydroxy, nitro, oxide, oxo,tri-C₁-C₄ alkylsilyl, trifluoromethoxy or trifluoromethyl.

Saturated heterocyclyl-C₀-C₄ alkyl is for example azepanyl, azetidinyl,aziridinyl, 3,4-dihydroxypyrrolidinyl, 2,6-dimethylmorpholinyl,3,5-dimethylmorpholinyl, dioxanyl, [1,4]dioxepanyl, dioxolanyl,4,4-dioxothiomorpholinyl, dithianyl, dithiolanyl,2-hydroxymethyl-pyrrolidinyl, 4-hydroxypiperidinyl,3-hydroxypyrrolidinyl, 4-methylpiperazinyl, 1-methyl-piperidinyl,1-methylpyrrolidinyl, morpholinyl, oxathianyl, oxepanyl, 2-oxo-azepanyl,2-oxo-imidazolidinyl, 2-oxo-oxazolidinyl, 2-oxo-piperidinyl,4-oxo-piperidinyl, 2-oxo-pyrrolidinyl, 2-oxo-tetrahydropyrimidinyl,4-oxo-thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, thiepanyl or thiomorpholinyl.

Partially saturated bicyclic heterocyclyl-C₀-C₄ alkyl is for example3,4-dihydro-2H-benzo[1,4]oxazinyl, 4,5,6,7-tetrahydrobenzofuranyl or4,5,6,7-tetrahydrobenzothiazolyl.

Unsaturated bicyclic heterocyclyl-C₀-C₄ alkyl is for examplebenzofuranyl, benzoimidazolyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl,benzo[b]thiophen, quinolinyl, imidazo[1,5-a]pyridinyl, indazolyl,indolyl or isoquinolinyl.

Unsaturated monocyclic heterocyclyl-C₀-C₄ alkyl is for exampleimidazolyl, oxazolyl, pyridyl, pyrrolyl, tetrazolyl, thiazolyl orthiophenyl.

C₂-C₈ alkenyl is for example ethenyl, propenyl, isopropenyl, butenyl,isobutenyl, secondary butenyl, tertiary butenyl, or a pentenyl, hexenylor heptenyl group.

C₂-C₈ alkynyl is for example ethynyl, propynyl, butynyl, or a pentynyl,hexynyl or heptynyl group.

C₁-C₈ alkoxy is for example C₁-C₅ alkoxy such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiarybutoxy or pentoxy, but may also be a hexoxy or heptoxy group.

C₁-C₈ alkoxycarbonyl is preferably C₁-C₄ alkoxycarbonyl such asmethoxycarbonyl, ethoxy-carbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycanbonyl, secondary butoxycarbonyl or tertiarybutoxycarbonyl.

C₁-C₄ alkoxycarbonyl-C₁-C₄ alkyl is for example methoxycarbonylmethyl orethoxycarbonyl-methyl, 2-methoxycarbonylethyl or 2-ethoxycarbonylethyl,3-methoxycarbonylpropyl or 3-ethoxycarbonylpropyl or4-ethoxycarbonylbutyl.

C₁-C₈ alkyl may be straight-chain or branched and/or bridged and is forexample methyl, ethyl; propyl, isopropyl, butyl, isobutyl, secondarybutyl, tertiary butyl, or a pentyl, hexyl or heptyl group.

C₀-C₈ alkylcarbonyl is for example formyl, acetyl, propionyl,propylcarbonyl, isopropyl-carbonyl, butylcarbonyl, isobutylcarbonyl,secondary butylcarbonyl or tertiary butylcarbonyl.

Carboxy-C₁-C₄ alkyl is for example carboxymethyl, 2-carboxyethyl, 2- or3-carboxypropyl, 2-carboxy-2-methylpropyl, 2-carboxy-2-ethylbutyl, or4-carboxybutyl, in particular carboxy-methyl.

C₃-C₈ cycloalkyl is preferably 3-, 5- or 6-membered cycloalkyl, such ascyclopropyl, cyclo-pentyl, cyclohexyl.

Halogen is for example fluorine, chlorine, bromine or iodine.

The compound groups mentioned below are not to be regarded as closed; onthe contrary, parts of these compound groups may be replaced by oneanother or by the definitions given above, or be omitted, in ameaningful way, e.g. to replace general by more specific definitions.The definitions mentioned apply within the scope of general chemicalprinciples such as, for example, the usual valencies of atoms.

R is preferably deuterium or hydrogen.R¹ is preferably aryl, very particularly preferably mono-, di- ortri-substituted phenyl, or heterocyclyl, very particularly preferablyoptionally mono-, di- or tri-substituted benzofuranyl,benzo[b]thiophenyl, benzoimidazolyl, benzo[d]isothiazolyl,benzo[d]isoxazolyl, benzo[b]thiophenyl, imidazolyl, indazolyl, indolyl,oxazolyl, pyridyl, pyrrolyl, thiazolyl or thiophenyl.R² is preferably C₁-C₈ alkoxy, hydroxy, C₁-C₈ alkyl, aryl-C₀-C₄ alkyl,deuterium, halogen, cyano or hydrogen.n is preferably a number 0 or 1. n is particularly preferably the number1.m is particularly preferably the number 1.

Preferred substituents for aryl or heterocyclyl are C₁-C₈ alkoxy, C₁-C₈alkyl, C₁-C₈ alkyl-carbonyl, C₁-C₈ alkylsulphonyl, optionallysubstituted aryl, cyano, halogen, optionally substituted heterocyclyl,nitro, oxide, trifluoromethyl, trifluoromethoxy or trimethylsilanyl.Very particularly preferred substituents for aryl or heterocyclyl areacetyl, bromine, chlorine, cyano, fluorine, methanesulphonyl, methoxy,nitro, oxazolyl, oxide, optionally substituted phenyl, optionallysubstituted tetrazolyl, optionally substituted thiazolyl or optionallysubstituted thiophenyl.

It is likewise preferred for R¹ to be a mono-, di- or tri-substitutedunsaturated heterocyclyl substituent, where the substituents arepreferably selected from the group consisting of C₁-C₈ alkyl, C₁-C₈alkoxy, C₁-C₈ alkoxycarbonyl, C₀-C₈ alkylcarbonyl, C₁-C₈ alkylsulphonyl,optionally substituted aryl, aryl-C₀-C₄ alkoxycarbonyl, cyano, halogen,optionally substituted heterocyclyl, hydroxy, nitro, oxide, oxo,tri-C₁-C₄ alkylsilyl, trifluoromethoxy and trifluoro-methyl.

Particularly preferred compounds of the formula (I) are those of thegeneral formula (Ia) and salts, preferably pharmaceutically acceptablesalts, thereof,

in which R, R¹, R², Q, m and n have the meanings indicated above forcompounds of the formula (I), and where the above preferences applyanalogously.* designates an asymmetric carbon atom.

The compounds of the formula (I) or (Ia) which possess at least oneasymmetric carbon atom can exist in the form of optically pureenantiomers, mixtures of enantiomers, or racemates. Compounds having asecond asymmetric carbon atom can exist in the form of optically purediastereomers, mixtures of diastereomers, diastereomeric racemates,mixtures of diastereomeric racemates, or meso compounds. The inventionembraces all of these forms. Mixtures of enantiomers, racemates,mixtures of diastereomers, diastereomeric racemates, or mixtures ofdiastereomeric racemates can be fractionated by conventional methods,such as by racemate resolution, column chromatography, thin-layerchromatography, HPLC and the like.

The compounds of the formula (Ia) have at least one asymmetric carbonatom, which is labelled “*”. A compound of the formula (Ia) is to beunderstood as a compound having a specific configuration around thedesignated asymmetric carbon atom. If a synthesis method is used whichleads to racemic compounds, the racemate resolution is carried out inaccordance with conventional methods, such as via a chiral HPLC column.Compounds of the formula (Ia) as described in the present inventionexhibit a pronounced aldosterone synthase and/or 11-β-hydroxylaseinhibitory activity and a low aromatase inhibitory activity. Theaforementioned aromatase inhibitory activity can, as the skilled workeris well aware and as described below, be comfortably determined usingthe commercial Cyp19 enzyme inhibition kit, preferably theCyp19/methoxy-4-trifluoromethyl-coumarin (MFC) high throughputinhibition kit (Becton Dickinson Biosciences, San Jose, Calif., USA) asdescribed hereafter. In the abovementioned inhibition kit, compounds ofthe formula (Ia) show an activity which is at least 10 times lowerpreferably 20 times lower, but more preferably 40 times lower than thecompounds of the formula (Ia) with the opposite configuration around theasymmetric carbon atom labelled “*”. A lower inhibiting activitycorresponds to a higher IC₅₀ value.

Example of CYP19 inhibition:

Example number IC50 value [nM] 18 8346.3 antipode of 18 4.8

The expression “pharmaceutically acceptable salts” embraces salts withorganic or inorganic acids, such as hydrochloric acid, hydrobromic acid,nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid,maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulphonic acid, p-toluenesulphonic acid and the like. Salts ofcompounds containing salt-forming groups are, in particular, acidaddition salts, salts with bases or else, if appropriate, if two or moresalt-forming groups are present, are mixed salts or inner salts.

The compounds of the formula (I) or (Ia) can be prepared in an analogousmanner to the preparation processes disclosed per se in the literature(1H-imidazol-4-yl)methanol by conversion into methyl(1H-imidazol-4-ylmethoxy)acetate followed by a Grignard addition,subsequent reduction (or vice versa) and ring closure (Scheme I).

Alternatively, the compounds of the formula (I) or (Ia) can be obtainedin an analogous manner to the preparation processes disclosed per se inthe literature starting from hydroxyphenylaceticacid derivatives byreaction with (1H-imidazol-4-yl)methanols followed by a reduction andsubsequent ring closure (Scheme II).

The compounds of the formula (I) or (Ia) which are tetrasubstituted canbe obtained in ah analogous manner to the preparation processesdisclosed per se in the literature starting from suitably substituted2-aminoethanols which can be converted, e.g. in analogy to org. Lett 7(5), (2005) pp. 937-939, into 5-spiromorpholin-3-ones, which are thenconverted, e.g. in analogy to the process disclosed in U.S. Pat. No.4,401,597, into compounds of the formula (I) or (Ia) (Scheme III).

Details of the specific preparation variants can be found in theexamples.

The compounds of the formula (I) or (Ia) can also be prepared inoptically pure form. Separation into antipodes is possible by methodsknown per se, either, preferably, at an early stage in synthesis, bysalt formation with an optically active acid such as, for example, (+)-or (−)-mandelic acid and separation of the diastereomeric salts byfractional crystallization, or, preferably, at a fairly late stage, byderivatization with a chiral auxiliary component, such as, for example,(+)- or (−)-camphanyl chloride and separation of the diastereomericproducts by chromatography and/or crystallization and subsequentcleavage of the bond to the chiral auxiliary. The pure diastereomericsalts and derivatives can be analysed to determine the absoluteconfiguration of the compound present, using customary spectroscopicmethods, with single-crystal X-ray spectroscopy representing oneparticularly appropriate method.

Salts are primarily the pharmaceutically acceptable or non-toxic saltsof compounds of the formula (I) or (Ia). Such salts are formed forexample by compounds of the formula (I) or (Ia) containing an acidicgroup, such as a carboxyl or sulpho group and are, for example, saltsthereof with suitable bases, such as non-toxic metal salts derived frommetals of group Ia, Ib, IIa and IIb of the Periodic Table of theElements; such as alkali metal salts, especially lithium, sodium orpotassium salts, alkaline earth metal salts, magnesium or calcium saltsfor example, and also zinc salts or ammonium salts, and additionallysalts formed with organic amines, such as unsubstituted orhydroxyl-substituted mono-, di- or trialkylamines, especially mono-, di-or tri-lower alkylamines, or with quaternary ammonium bases, e.g.methyl-, ethyl-, diethyl- or triethylamine, mono-, bis- ortris(2-hydroxyl-lower alkyl)amines, such as ethanol-amine,diethanolamine or triethanolamine, tris(hydroxylmethyl)methylamine or2-hydroxyl-tertiary-butylamine, N,N-di-lower alkyl-N-(hydroxyl-loweralkyl)amine, such as N,N-di-N-dimethyl-N-(2-hydroxylethyl)amine, orN-methyl-D-glucamine, or quaternary ammonium hydroxides, such astetrabutylammonium hydroxide. The compounds of the formula (I) or (Ia)containing a basic group, such as an amino group, can form acid additionsalts, with suitable inorganic acids for example, such as hydrohalicacid, such as hydrochloric acid, hydrobromic acid, or sulphuric acidwith replacement of one or both protons, phosphoric acid withreplacement of one or more protons, orthophosphoric acid ormetaphosphoric acid for example, or pyrophosphoric acid with replacementof one or more protons, or with organic carboxylic, sulphonic orphosphonic acids or N-substituted sulphamic acids, e.g. acetic acid,propionic acid, glycolic acid, succinic acid, maleic acid,hydroxylmaleic acid, methylmaleic acid, fumaric acid, malic acid,tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid,4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid,embonic acid, nicotinic acid, isonicotinic acid, and also amino acids,such as the α-amino acids specified earlier on, and alsomethane-sulphonic acid, ethanesulphonic acid, 2-hydroxylethanesulphonicacid, ethane-1,2-disulphonic acid, benzenesulphonic acid,4-toluenesulphonic acid, naphthalene-2-sulphonic acid, 2- or3-phosphoglycerate, glucose 6-phosphate, N-cyclohexylsulphamic acid (toform cyclamates), or with other acidic organic compounds, such asascorbic acid. Compounds of the formula (I) or (Ia) containing acidicand basic groups can also form inner salts.

Isolation and purification can also be carried out usingpharmaceutically unsuitable salts.

The compounds of the formula (I) or (Ia) also include those compounds inwhich one or more atoms have been replaced by their stable,non-radioactive isotopes: for example, a hydrogen atom by deuterium.

Prodrug derivatives of the presently described compounds are derivativesthereof which when employed in vivo release the original compound as aresult of a chemical or physiological process. A prodrug may beconverted into the original compound, for example, when a physiologicalpH is reached or as a result of enzymatic conversion. Examples ofpossible prodrug derivatives include esters of freely availablecarboxylic acids, S- and O-acyl derivatives of thiols, alcohols orphenols, the acyl group being defined as above. Preference is given topharmaceutically useful ester derivatives which are converted bysolvolysis in physiological medium into the original carboxylic acid,such as, for example, lower alkyl esters, cycloalkyl esters, loweralkenyl esters, benzyl esters, mono- or disubstituted lower alkylesters, such as lower ω-(amino, mono- or dialkylamino, carboxyl, loweralkoxycarbonyl)-alkyl esters or such as lower α-(alkanoyloxy,alkoxycarbonyl or dialkylaminocarbonyl)alkyl esters; pivaloyloxymethylesters and similar esters are conventionally used as ester derivativesof this kind.

Because of the close relationship between a free compound, a prodrugderivative and a salt compound, a defined compound in this inventionalso includes its prodrug derivative and salt form, insofar as this ispossible and appropriate.

Aldosterone is a steroidal hormone which is synthesized in the zonaglomerulosa cells of the adrenal cortex by the enzyme aldosteronesynthase (CYP11B2). Aldosterone production and secretion is regulated bythe adrenocorticotropic hormone (ACTH), angiotensin II, potassium andsodium ions. The primary biological function of aldosterone is theregulation of the salt balance, with aldosterone controlling thereabsorption of sodium ions from the renal filtrate and the secretion ofpotassium ions into the renal filtrate. The state of excessivealdosterone secretion, also called hyperaldosteronism, can lead to highblood pressure, hypokalemia, alkalosis, muscle weakness, polyuria,polydipsia, oedemas, vasculitis, increased collagen formation, fibrosisand endothelial dysfunction.

The chemical compounds described in this invention inhibit thecytochrome P450 enzyme aldosterone synthase (CYP11B2) and can thereforebe used to treat states induced by aldosterone. The compounds describedcan be employed for preventing, for delaying the progression of ortreating states such as hypokalaemia, hypertension, congestive heartfailure, acute and—in particular—chronic renal failure, cardiovascularrestenosis, atherosclerosis, metabolic syndrome (syndrome X), adiposity(obesity), vasculitis, primary and secondary hyperaldosteronism,nephropathy, myocardial infarction, coronary heart disease, increasedcollagen formation, fibrosis, vascular and coronary tissue changes(remodelling) secondary to high bipod pressure, endothelial dysfunction,and oedemas secondary to cirrhosis, nephrosis and congestive heartfailure.

Cortisol is a steroidal hormone which is synthesized almost exclusivelyin the zona fasciculata cells of the adrenal cortex by the cytochromeP450 enzyme 11-β-hydroxylase (CYP11B1). Cortisol production is regulatedby ACTH. The primary biological function of cortisol is to regulate theproduction and the provision of carbohydrates for the brain and othermetabolically active tissues. Increased Cortisol production andsecretion is a normal physiological response to stress and leads to theessential mobilization of fats, proteins and carbohydrates to coverincreased physical energy demand. Chronically excessive Cortisol releasedescribes the condition of Cushing's syndrome. Cushing's syndrome maycome about on the one hand as a result of Cortisol hypersynthesis, whichmay be generated by an adrenocortical tumour, or on the other hand asthe consequence of excessive stimulation of the adrenal cortex by ACTH.The first form is referred to as primary hypercortisolism, the secondform as secondary hypercortisolism. An excessive and persistent Cortisolsecretion may also accompany a stress response, which can lead todepression and the suppression of the immune system.

The chemical compounds described in this invention inhibit the enzyme11-β-hydroxylase (CYP11B1) and may therefore, owing to the inhibition ofCortisol synthesis, be employed for preventing, for delaying theprogression of or treating Cushing's syndrome and also the physical andmental consequences of excessive and persistent Cortisol secretion instates of stress.

The inhibition of aldosterone synthase (CYP11B2), as well as11-β-hydroxylase (Cyp11B1) and aromatase (Cyp19) by herein describedcompounds may be measured by the following in vitro assay.

The cell line NCI-H295R was originally derived from an adrenal carcinomaand was sub-sequently characterized in the literature for the induciblesecretion of steroidal hormones and the presence of the key enzymesnecessary for steroidogenesis. These include Cyp11A (cholesterolside-chain cleavage), Cyp11B1 (steroid 11β-hydroxylase), Cyp11B2(aldo-sterone synthase), Cyp17 (steroid 17α-hydroxylase and 17,20lyase), Cyp19 (aromatase), Cyp21B2 (steroid 21-hydroxylase) and 3β-HSD(hydroxysteroid dehydrogenase). The cells have the physiologicalcharacteristics of zonally undifferentiated human fetal adrenal cells,with the ability to produce the steroid hormones of each of the threephenotypically distinct zones found in the adult adrenal cortex.

The NCI-H295R cells (American Type Culture Collection, ATCC, Rockville,Md., USA) are cultured in Dulbecco's Modified Eagle'Ham F-12 medium(DME/F12) that is supplemented with Ultroser SF serum (Soprachem,Cergy-Saint-Christbphe, France) as well as insulin, transferrin,selenite (I-T-S, Becton Dickinson Biosiences, Franklin Lakes, N.J., USA)and antibiotics in 75 cm² cell culture flasks at a temperature of 37° C.and a 95% air/5% CO₂ humidified atmosphere. The cells are subsequentlytransferred to a 24-well plate and seeded in the presence of DME/F12medium that is supplemented with 0.1% bovine serum albumin instead ofUltroser SF serum. The experiment is initiated by incubating the cellsfor 72 hours in DME/F12 medium supplemented with 0.1% bovine serumalbumin and test compounds in the presence of cell stimulatory agents.The test compound is added in a concentration range of 0.2 nanomolar to20 micromolar. Angiotensin-II (e.g. at 10 or 100 nanomolarcon-centration), potassium ions (e.g. at 16 millimolar), forskolin (e.g.at 10 micromolar) or a combination of two agents may serve ascell-stimulatory agents. The cellular secretion of aldosterone,Cortisol, corticosterone and estradiol/estrone into the cell culturemedium can be quantitatively assessed with commercially availableradioimmunoassays and specific anti-bodies (e.g. Diagnostics ProductsCorporation, Los Angeles, Calif., USA) according to the manufacturer'sinstructions.

The degree of secretion of a selective steroid is used as a measure ofenzyme activity, respectively enzyme inhibition, in the presence orabsence of a test compound. The dose-dependent enzyme inhibitoryactivity of a compound is reflected in an inhibition curve that ischaracterized by an IC₅₀ value. The IC₅₀ values for active testcompounds are generated by simple linear regression analysis toestablish inhibition curves without data weighting. The inhibition curveis generated by fitting a 4-parameter logistic function to the raw dataof the samples using the least squares approach. The function isdescribed as follows:

Y=(d−a)/((1+(x/c)^(−b))+a)

with:a=minimumb=slopec=IC₅₀d=maximumx=inhibitor concentrations

The compounds of the present invention show in the herein described invitro test systems inhibitory activities with IC₅₀ values foraldosterone synthesis inhibition ranging from 10⁻⁴ to 10⁻¹⁰ mol/l, andIC₅₀ values for Cortisol synthesis inhibition ranging from 10⁻⁴ to 10⁻¹⁰mol/l.

Additionally, the in vitro inhibition of aromatase activity of thecompounds of the present invention can be demonstrated by using acommercial Cyp19 enzyme inhibition kit. TheCyp19/methoxy-4-trifluoromethyl-coumarin (MFC) high throughputinhibition kit (Becton Dickinson Biosciences, San Jose, Calif., USA),for example, is designed to screen for potential inhibitors of Cyp19catalytic activity in a 96-well format. The kit includes recombinanthuman Cyp19 enzyme in the form of supersomes, a fluorescent P450substrate, an NADPH regenerating system, a reaction buffer and a stopreagent. MFC, the fluorogenic substrate is rapidly converted by Cyp19supersomes to the highly fluorescent product 7-hydroxy-4-trifluoromethylcoumarin (7-HFC). The execution of the assay in the presence of variousconcentrations of inhibitor compounds ranging from 0.2 nanomolar to 20millimolar occurs according to the manufacturer's instructions.

The inhibition curve is generated by fitting a 4-parameter logisticfunction to the raw data of the samples using the least squaresapproach. The function is described as follows:

Y=(d−a)/((1+(x/c)^(−b))+a)

with:a=minimal data valuesb=slopec=IC₅₀d=maximal data valuesx=inhibitor concentrations

The aldosterone- and corticosterone-suppressing activity of hereindescribed compounds may be assessed with the following in vivo protocol.

Adult male Wistar rats weighing between 250 and 350 grams are kept underthe usual 12 hour light and 12 hour dark conditions at a temperature of23° C.±2° C. On the first day of the experiment, the animals receive asubcutaneous injection of a depot ACTH product in a dose of 1.0 mg/kgweight (SYNACTHEN-Depot, Novartis, Basel, CH) 16 hours prior to theadministration of a test compound. Pilot studies showed that this ACTHdose significantly increased plasma aldosterone and corticosteronelevels by 5- to 20-fold over a period of at least 18 hours. Analternative method to stimulate aldosterone secretion consists insubjecting rats to a low salt diet for 48 hours and applying thediuretic furosemide at 10 mg/kg by subcutaneous or intraperitonealadministration 16 hours, respectively 2 hours prior to the start of theexperiment. On the second day of the experiment, the animals are dividedinto test groups of 5 animals and subjected to a first bleed 1 hourprior to the administration of test compound. Subsequently, and 16 hoursafter the injection of the ACTH product, the animals receive eithervehicle or test compound dissolved in vehicle in a variable dose rangefrom 0.02 to 20 mg/kg by oral gavage. The animals are bled two moretimes from the vena subclavia under isoflurane anaesthesia 2 and 6 hoursafter dosing. The blood is collected in heparin-treated tubes. Theplasma samples are obtained by centrifugation and stored at −20° C. Analternative method to bleed animals time-dependently consists in usinganimals that are chronically carotid catheterized which allows theperiodical sampling of up to 0.2 ml of blood using an AccuSampler (DiLabEurope, Lund, Sweden). The blood sampling with the AccuSampler may occur1 hour prior to the administration of a test compound and 2, 4, 6, 8,12,16 and 24 hours thereafter. The blood samples are anticoagulated withheparin and centrifuged. The aldosterone and corticosteroneconcentrations of the plasma samples can be determined with aradioimmunoassay as described above for the in vitro test systems.

The selective suppression of plasma steroid levels as for instancealdosterone in comparison to corticosterone may serve as a measure forin vivo bioavailability and pharmacodynamic enzyme inhibitory activityof the herein described compounds. The evaluation of the data may occurrelative to the application of vehicle or quantitatively bydetermination of the area under the curve (AUG).

Examples of suppression of aldosterone and corticosterone levels:

Compound of Dose Aldosterone levels Corticosterone levels Example (mg/kgp.o.) (% change⁺ at 2 h) (% change⁺ at 2 h) 14 4 −58 −7 16 4 −67 −9 ⁺Theresulting changes in plasma aldosterone, respectively corticosterone,levels upon oral administration of a test compound are expressed aspercent (%) change that is defined by the ratio of the [(plasma steroidlevel 2 hours after compound administration) − (plasma steroid level 1hour prior to compound administration)] divided by (plasma steroid level1 hour prior to compound administration).

In order to achieve the desired effects in a patient to be treated, thecompounds of the pre-sent invention can be administered orally orenterally, such as, for example, intravenously, intraperitoneally,intramuscularly, rectally, subcutaneously or else by direct injection ofthe active substance locally into tissues or tumours. The term patientencompasses warm-blooded species and mammals such as, for example,human, primate, bovine, dog, cat, horse, sheep, mouse, rat and pig. Thecompounds can be administered as pharmaceutical product or beincorporated into an administration device which ensures sustainedrelease of the compound. The amount of substance to be administered canvary over a wide range and represent every effective dose. Depending onthe patient to be treated or the condition to be treated and mode ofadministration, the dose of the effective substance each day can bebetween about 0.005 and 50 milligrams per kilogram of body weight, butis preferably between about 0.05 and 5 milligrams per kilogram of bodyweight each day.

For oral administration, the compounds can be formulated in solid orliquid pharmaceutical forms such as, for example, as capsules, pills,tablets, coated tablets, granules, powders, solutions, suspensions oremulsions. The dose of a solid pharmaceutical form can be one usual hardgelatine capsule which may be filled with active ingredients andexcipients such as lubricants and fillers, such as, for example,lactose, sucrose and maize starch: Another form of administration may berepresented by tableting of the active substance of the presentinvention. The tableting can take place with conventional tabletingexcipients such as, for example; lactose, sucrose, maize starch;combined with binder from gum acacia, maize starch or gelatine,disintegrants such as potato starch or crosslinked polyvinylpyrrolidone(PVPP) and lubricants such as stearic acid or magnesium stearate.

Examples of excipients suitable for soft gelatine capsules are vegetableoils, waxes, fats, semisolid and liquid polyols etc.

Examples of excipients suitable for producing solutions and syrups arewater, polyols, sucrose, invert sugar, glucose etc.

For rectal administration, the compounds can be formulated in solid orliquid pharmaceutical forms such as, for example, suppositories.Examples of excipients suitable, for suppositories are natural orhardened oils, waxes, fats, semiliquid or liquid polyols etc.

For parenteral administration, the compounds can be formulated asinjectable dosage of the active ingredient in a liquid or suspension.The preparations usually comprise a physiologically tolerated sterilesolvent which may comprise a water-in-oil emulsion; with or withoutsurfactant, and other pharmaceutically acceptable excipients. Oils whichcan be used for such preparations are paraffins and triglycerides ofvegetable; animal or synthetic origin, such as, for example, peanut oil,soya oil and mineral oil. Injectable solutions generally comprise liquidcarriers such as, preferably, water, saline, dextrose or related sugarsolutions, ethanol and glycols such as propylene glycol or polyethyleneglycol.

The substances may be administered as transdermal patch system, as depotinjection or implant if the formulation makes sustained delivery of theactive ingredient possible. The active substance can be compressed asgranules or to narrow cylinders and be administered subcutaneously orintramuscularly as depot injection or implant.

The pharmaceutical products may in addition also comprise preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, aromatizing agents, salts tochange the osmotic pressure, buffers, coating agents or antioxidants.They may also comprise other therapeutically valuable substances too.

The compounds of the invention described herein permit the followingmethods of use:

-   -   as therapeutic combination in the form of a product or of a kit        which is composed of individual components consisting of a        compound described herein, in free form or as pharmaceutically        acceptable salt, and at least one pharmaceutical form whose        active ingredient has a blood pressure-lowering, an inotropic,        an antidiabetic, an obesity-reducing or a lipid-lowering effect,        which can be used either simultaneously or sequentially. The        product and the kit may comprise instructions for use.    -   as method for combined use, such as, for example, in        simultaneous or sequential succession, of a therapeutically        effective amount of a compound described herein, in free or in        pharmaceutically acceptable salt form, and of a second active        ingredient with blood pressure-lowering, inotropic,        antidiabetic, obesity-reducing or lipid-lowering effect.

The compounds described herein and their pharmaceutically acceptablesalts can be used in combination with

(i) one or more blood pressure-lowering active ingredients, as such forexample:

-   -   renin inhibitors such as aliskiren;    -   angiotensin II receptor blockers such as candesartan,        irbesartan, olmesartan, losartan, valsartan, telmisartan etc.;    -   ACE inhibitors such as quinapril, ramipril, trandolapril,        lisinopril, captopril, enalapril etc.;    -   calcium antagonists such as nifedipine, nicardipine, verapamil,        isradipine, nimodipine, amlodipine, felodipine, nisoldipine,        diltiazem, fendiline, flunarizine, perhexyline, gallopamil etc.;    -   diuretics such as hydrochlorothiazide, chlorothiazide,        acetazolamide, amiloride, bumetanide, benzthiazide, etacrynic        acid, furosemide, indacrinone, metolazone, triamterene,        chlorthalidone, etc.;    -   aldosterone receptor blockers such as spironolactone,        eplerenone; endothelin receptor blockers such as bosentan;    -   phosphodiesterase inhibitors such as amrinone, sildenafil;    -   direct vasodilators such as dihydralazine, minoxidil, pinacidil,        diazoxide, nitroprusside, flosequinan etc.,    -   α- and β-receptor blockers such as phentolamine,        phenoxybenzamine, prazosin, doxazosin, terazosin, carvedilol,        atenolol, metoprolol, nadolol, propranolol, timolol, carteolol        etc.;    -   neutral endopeptidase (NEP) inhibitors;    -   sympatholytics such as methyldopa, clonidine, guanabenz,        reserpine        (ii) one or more agents having inotropic activity, as such for        example:    -   cardiac glycosides such as digoxin;    -   β-receptor stimulators such as dobutamine    -   thyroid hormone such as thyroxine        (iii) one or more agents having antidiabetic activity, as such        for example:    -   insulins such as insulin aspart, insulin human, insulin lispro,        insulin glargirie and further fast-, medium- and long-acting        insulin derivatives and combinations    -   insulin sensitizers such as rosiglitazone, pioglitazone;    -   sulphonylureas such as glimepiride, chlorpropamide, glipizide,        glyburide etc.;    -   biguanides such as metformin;    -   glucosidase inhibitors such as acarbose, miglitol;    -   meglitinides such as repaglinide, nateglinide;        (iv) one or more obesity-reducing ingredients, as such for        example:    -   lipase inhibitors such as orlistat;    -   appetite suppressants such as sibutramine, phentermine;        (v) one or more lipid-lowering ingredients, such as, for        example,    -   HMG-CoA reductase inhibitors such as lovastatin, fluvastatin,        pravastatin, atorvastatin, simvastatin, rosuvastatin etc.;    -   fibrate derivatives such as fenofibrate, gemfibrozil etc.;    -   bile acid-binding active ingredients such as colestipol,        colestyramine, colesevelam    -   cholesterol absorption inhibitors such as ezetimibe    -   nicotinic acid such as niacin        and other agents which are suitable for the treatment of high        blood pressure, heart failure or vascular disorders associated        with diabetes and renal disorders, such as acute or chronic        renal failure, in humans and animals. Such combinations can be        used separately or in products which comprise a plurality of        components.

The compounds described herein and their pharmaceutically acceptablesalts can additionally be used in combination with

-   -   (i) a diagnostic test system which permits quantitative        determination of the plasma aldosterone level (PAC, plasma        aldosterone concentration)    -   (ii) a diagnostic test system which permits quantitative        determination of the plasma renin level (PRC, plasma renin        concentration)    -   (iii) a diagnostic test system which permits quantitative        determination of the plasma renin activity (PRA, plasma renin        activity)    -   (iv) a diagnostic test system which permits quantitative        determination of the plasma aldosterone/renin level (ARC,        aldosterone renin concentration)    -   (v) a diagnostic test system which permits quantitative        determination of the plasma aldosterone/renin activity (ARR,        aldosterone to renin activity ratio)    -   (vi) a diagnostic test system which permits quantitative        determination of the plasma cortisol level (PCC, plasma Cortisol        concentration)

Such diagnosis-therapy combinations can be used separately or inproducts which comprise a plurality of components.

EXAMPLES

The following examples illustrate the present invention. Alltemperatures are stated in degrees Celsius, pressures in mbar. Unlessmentioned otherwise, the reactions take place at room temperature. Theabbreviation “Rf=xx(A)” means for example that the Rf is found insolvent system A to have the value xx. The proportion of solvents to oneanother is always stated in fractions by volume. Chemical names of endproducts and intermediates were generated with the aid of the AutoNom2000 (Automatic Nomenclature) program.

HPLC gradients on Hypersil BDS C-18 (5 μm); column: 4×125 mm:

-   (I) 90% water 710% acetonitrile * to 0% water */100% acetonitrile *    in 5 minutes+2.5 minutes (1.5 ml/min)-   (II) 99% water 71% acetonitrile * to 0% water */100% acetonitrile *    in 10 minutes+2 minutes (1.5 ml/min)

HPLC gradients on Synergi 4 μm POLAR-RP 80A; column 4.60×100 mm:

-   (III) 90% water 710% acetonitrile * to 0% water */100%    acetonitrile * in 5 minutes+2.5 minutes (1.5 ml/min)    * contains 0.1% trifluoroacetic acid

The abbreviations used are as follows:

-   Rf ratio of distance traveled by a substance to distance of the    eluent from the starting point in thin-layer chromatography-   Rt retention time of a substance in HPLC (in minutes)-   m.p. melting point (temperature)

Example 1 4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)benzonitrile

A solution of 1.00 mmol of1-(4-cyanophenyl)-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethylmethanesulphonate in 5 ml of N,N-dimethylformamide is mixed with 2.50mmol of caesium carbonate and heated at 80° C. for 6 hours. The reactionmixture is cooled to room temperature, diluted with water and extractedwith ethyl acetate (2×). The combined organic phases are dried withsodium sulphate and evaporated. The title compound is obtained from theresidue as yellowish crystals by flash chromatography (SiO₂ 60F).Rf=0.61 (dichloromethane-methanol-25% aqueous ammonia solution200:10:1); Rt=3.54 (gradient II).

The starting materials are prepared as follows:

a) 1-(4-Cyanophenyl)-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethylmethanesulphonate

4 mmol of triethylamine and 2.00 mmol of methanesulphonyl chloride areadded to a solution of 1.00 mmol of4-[1-hydroxy-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrile in10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0°C. for 1 hour, diluted with dichloro-methane, washed with 1N HCl, driedwith sodium sulphate and evaporated. The crude title compound is usedwithout further purification in the next stage. Rf=0.43(dichloromethane-methanol 95:5); Rt=4.46 (gradient I).

b1) 4-[1-Hydroxy-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]-benzonitrile

Sodium borohydride is added in portions to a solution of 1 mmol of4-[2-(1-trityl-1H-imidazol-4-ylmethoxy)acetyl]benzonitrile in 12 ml ofethanol at 0° C. The reaction solution is stirred at room temperaturefor 12 hours, then poured into ice-water and stirred for 15 minutes. Themixture is adjusted to pH 5 by adding glacial acetic acid and extractedwith tert-butyl methyl ether (2×). The combined organic phases arewashed with water and brine, dried over sodium sulphate and evaporated.The title compound is identified from the residue on the basis of the Rfby flash chromatography (SiO₂ 60F).

c1) 4-[2-(1-Trityl-1H-imidazol-4-ylmethoxy)acetyl]benzonitrile

A solution of 14 mmol of 4-iodobenzonitrile [3058-39-7] in 20 ml oftetrahydrofuran is cooled to −30° C., and 14.80 mmol ofi-propylmagnesium chloride (2M in tetrahydrofuran) are added. Themixture is stirred at −30° C. for 60 minutes and a solution, precooledto −30° C., of 10.0 mmol ofN-methoxy-N-methyl-2-(1-trityl-1H-imidazol-4-ylmethoxy)acetamide in 30ml of tetrahydrofuran is added. The mixture is stirred at −30° C. for 30minutes, and then the reaction mixture is warmed to room temperature andquenched with saturated aqueous ammonium chloride, solution. The phasesare separated, and the aqueous phase is extracted with ethyl acetate(3×). The combined organic phases are washed with brine, dried withmagnesium sulphate and evaporated. The title compound is identified fromthe residue on the basis of the Rf by flash chromatography (SiO₂ 60F).

d1) N-Methoxy-N-methyl-2-(1-trityl-1H-imidazol-4-ylmethoxy)acetamide

A solution of 4.03 mmol of (1-trityl-1H-imidazol-4-ylmethoxy)acetic acidand 4.44 mmol of N,O-dimethylhydroxylamine hydrochloride in 100 ml ofdichloromethane is mixed with 20.2 mmol of triethylamine and 4.44 mmolof propanephosphonic acid cyclic anhydride [68957-94-8] (50% in ethylacetate). The reaction mixture is stirred at room temperature for 3hours and diluted with dichloromethane. The phases are separated and theorganic phase is washed with 1M HCl and brine, dried with sodiumsulphate and evaporated. The title compound is obtained as a paleyellowish solid from the residue by flash chromatography (SiO₂ 60F).Rf=0.45 (dichloromethane-methanol 95:5); Rt=4.11 (gradient I).

e1) (1-Trityl-1H-imidazol-4-ylmethoxy)acetic acid

A mixture of 1.0 mmol of ethyl (1-trityl-1H-imidazol-4-ylmethoxy)acetatein 16 ml of tetra-hydrofuran and 16 ml of 2N NaOH is stirred underreflux for 18 hours. The reaction mixture is cooled and thetetrahydrofuran is distilled off. 20 ml of 2N HCl are added to theaqueous residue, and the resulting suspension is diluted with tert-butylmethyl ether. The solid is filtered off and the filter cake is washedwith water and tert-butyl methyl ether and dried. The title compound isobtained as a yellowish solid. Rf=0.02 (ethyl acetate-heptane 2:1);

Rt=3.86 (gradient I).

f) Ethyl (1-trityl-1H-imidazol-4-ylmethoxy)acetate

58.0 mmol of sodium hydride (60% dispersion in paraffin) are added inportions to a solution of 30.0 mmol of(1-trityl-1H-imidazol-4-yl)methanol [33769-07-2] in 300 ml ofN,N-dimethyl-formamide at 20° C. The mixture is stirred at 20° C. for1.5 hours. 50.0 mmol of ethyl bromo-acetate [105-36-2] and 6.00 mmol ofpotassium iodide are added, and the mixture is stirred at roomtemperature for 16 hours. A further 58.0 mmol of sodium hydride and 50mmol of ethyl bromoacetate are added and the mixture is stirred againfor 16 hours. The reaction mixture is poured into water and extractedwith tert-butyl methyl ether (2×). The combined organic phases arewashed with water and brine, dried with magnesium sulphate andevaporated. The title compound is obtained as a brown oil from theresidue by flash chromatography (SiO₂ 60F). Rf=0.20 (ethylacetate-heptane 2:1), Rt=4.32 (gradient I).

Alternative syntheses for4-[1-hydroxy-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrile:

b2) 4-[1-Hydroxy-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]-benzonitrile

1.5 mmol of tetrabutylammonium fluoride (1M solution in tetrahydrofuran)are added to a solution of 1 mmol of4-[1-(tert-butyldimethylsilanyloxy)-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrilein 5 ml of tetrahydrofuran, and the solution is stirred at roomtemperature for 1 hour. The reaction solution is then diluted with waterand extracted with tert-butyl methyl ether (2×). The combined organicphases are dried with sodium sulphate and evaporated. The title compoundis identified from the residue on the basis of the Rf by flashchromatography (SiO₂ 60F).

c2)4-[1-(tert-Butyldimethylsilanyloxy)-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrile

A solution of 1.27 mmol of titanium tetrachloride in 1.5 ml ofdichloromethane is added to a solution of 2.61 mmol of trimethylsilyltrifluoromethanesulphonate in 1 ml of dichloromethane at 0° C. Themixture is stirred at room temperature for 4 hours and then cooled to 0°C. A solution of 0.83 mmol of 1-trityl-1H-imidazol-4-ylmethyl(tert-butyldimethylsilyloxy)(4-cyanophenyl)acetate and 4.17 mmol oftriethylsilane in 2 ml of dichloromethane is added, and the reactionmixture is stirred at room temperature for 20 hours. The reactionmixture is poured into ice-water and extracted with ethyl acetate (2×).The combined organic phases are washed with water and brine; dried withsodium sulphate and evaporated. The title compound is identified fromthe residue on the basis of the Rf by flash chromatography (SiO₂ 60F).

d2) 1-Trityl-1H-imidazol-4-ylmethyl(tert-butyldimethylsilanyloxy)(4-cyanophenyl)acetate

5.0 mmol of triethylamine and 1.0 mmol propanephosphonic acid cyclicanhydride [68957-94-8](50% in ethyl acetate) are added to a solution of1.0 mmol of (1-trityl-1H-imidazol-4-yl)methanol [33769-07-2] and 1.0mmol of (tert-butyldimethylsilanyloxy)(4-cyanophenyl)acetic acid in 20ml of dichloromethane. The reaction mixture is stirred at roomtemperature for 3 hours and diluted with dichloromethane. The phases areseparated and the organic phase is washed with 1M HCl and brine, driedwith sodium sulphate and evaporated. The title compound is identifiedfrom the residue on the basis of the Rf by flash chromatography (SiO₂60F).

e2) tert-Butyldimethylsilanyloxy)(4-cyanophenyl)acetic acid

A mixture of 1.0 mmol of methyl(tert-butyldimethylsilanyloxy)(4-cyanophenyl)acetate [435344-67-5] in 12ml of tetrahydrofuran, 12 ml of methanol and 12 ml of water is mixedwith 4 mmol of lithium hydroxide and stirred at 0° C. for 2 hours. 20 mlof 2N HCl are added to the reaction mixture, which is extracted withtert-butyl methyl ether (3×). The combined organic phases are washedsuccessively with water and brine, dried with sodium sulphate, filteredand evaporated, and the crude title Compound is identified on the basisof the Rf. The crude title compound is used without further purificationin the next stage.

b3) 4-[1-Hydroxy-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrile

20.0 mmol of sodium hydride (60% dispersion in paraffin) are added to asolution of 20.0 mmol of (1-trityl-1H-imidazol-4-yl)methanol[33769-07-02] in 120 ml of absolute N,N-dimethylformamide under argon.The mixture is heated at 100° C. for 1 hour and then cooled to 40° C. Asolution of 20.0 mmol of 4-oxiranylbenzonitrile [52695-39-3] in 10 ml ofabsolute N,N-dimethylformamide is added dropwise at 35-40° C., and thereaction mixture is stirred at 40° C. for 15 minutes. The reactionmixture is cooled to room temperature, poured into ice-water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over sodium sulphate and evaporated. Thetitle compound is obtained as a white solid from the residue by flashchromatography (SiO₂ 60F). Rf=0.29 (dichloromethane-methanol 95:5);Rt=4.26 (gradient I).

The following compounds are prepared in analogy to the process describedin example 1:

2 4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]thiazin-5-yl)benzonitrile

starting from (1-trityl-1H)-imidazol-4-ylmethylsulphanyl)acetic acid[478909-58-9].

6 4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)-2-fluorobenzonitrile

starting from 2-fluoro-4-iodobenzonitrile [137553-42-5].

7 5-(4-Nitrophenyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine

starting from 1-iodo-4-nitrobenzene [636-98-6].

9 5-(4-Methanesulphonylphenyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine

starting from 1-iodo-4-methanesulphonylbenzene [64984-08-3].

104-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)-2,6-difluorobenzonitrile

starting from 2,6-difluoro-4-iodobenzonitrile [14743-50-3].

114-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)-2-methoxybenzonitrile

starting from 4-iodo-2-methoxybenzonitrile [677777-44-5].

12 5-Benzo[b]thiopen-3-yl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine

starting from 3-iodobenzo[b]thiophene [36748-88-6].

13 5-(7-Fluorobenzofuran-3-yl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine

starting from 3-bromo-7-fluorobenzofuran [1288851-92-3].

14 5-(4-Fluorophenyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine

starting from 2-(4-fluorophenyl)oxirane [18511-62-1]. Beige solid.Rf=0.27 (dichloromethane-methanol 95:5); Rt=3.94 (gradient II).

15 5-(3,4-Difluorophenyl)-5,6-dihydro-6H-imidazo[5,1-c][1,4]oxazine

starting from 2-(3,4-difluorophenyl)oxirane [111991-13-0]. Beige solid.Rf=0.31 (dichloromethane-methanol 95:5); Rt=4.20 (gradient II).

17 4-(5,6-Dihydro-8H-imidazo[5,1-c][0,4]oxazin-5-yl)-phthalonitrile

starting from 4-iodo-phthalonitrile [69518-17-8].

Example 34-(5-Methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)benzonitrile

2 mmol of zinc cyanide and 5 mol % of tetrakis(triphenylphosphine)palladium(0) are added to a solution of 1 mmol of4-(5-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenyltrifluoromethanesulphonate in 20 ml of toluene, and the mixture isdegassed and heated at 120° C. for 20 hours. The reaction solution iscooled and stirred with water, and tert-butyl methyl ether. The phasesare separated and the aqueous phase is extracted with tert-butyl methylether (2×). The organic phases are combined and evaporated to dryness.The title compound is identified from the residue on the basis of the Rfby flash chromatography (SiO₂ 60F).

The starting materials are prepared as follows:

a) 4-(5-Methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenyltrifluoromethanesulphonate

2.2 mmol of N-phenylbis(trifluoromethanesulphonimide) and 2.5 mmol oftriethylamine are added to a solution of 2 mmol of4-(5-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenol in 20ml of dichloromethane under argon. The reaction solution is stirred atroom temperature for 18 hours and then evaporated to dryness. The titlecompound is identified from the residue on the basis of the Rf by flashchromatography (SiO₂ 60F).

b) 4-(5-Methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenol

A mixture of 3.6 mmol of5-(4-methoxyphenyl)-5-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]-oxazineand 10 ml of trimethylsilyl iodide in 40 ml of acetonitrile is heated toreflux for 24 hours. 10 ml of methanol are cautiously added and heatingto reflux is continued for 30 minutes. The reaction mixture isevaporated. The title compound is identified from the residue on thebasis of the Rf by flash chromatography (SiO₂ 60F).

c)5-(4-Methoxyphenyl)-5-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine

A mixture of 1.9 mmol of5-(4-methoxyphenyl)-5-methyl-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazineand 3 g of manganese dioxide in 50 ml of toluene is heated to reflux for3.5 hours. The reaction mixture is cooled to room temperature, the solidis filtered off through Hyflo, and the filtrate is evaporated. The crudetitle compound is obtained as a yellow oil from the residue and isemployed without further purification in the next stage. Rf=0.31(dichloromethane-methanol-25% aqueous ammonia solution 200:10:1),Rt=2.66 (gradient I)

d1)5-(4-Methoxyphenyl)-5-methyl-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazine

A solution of 31 mmol ofC-[5-(4-methoxyphenyl)-5-methylmorpholin-3-yl]methylamine and 31 mmol ofN,N-dimethylformamide dimethyl acetal in 50 ml of dichloromethane isheated to reflux for 6 hours. The reaction mixture is cooled to roomtemperature and evaporated. The crude title compound is obtained as ayellow oil from the residue and is employed without further purificationin the next stage, Rf=0.17 (dichloromethane-methanol-25% aqueous ammoniasolution 200:20:1), Rt=2.61 (gradient I)

e1) C-[5-(4-Methoxyphenyl)-5-methylmorpholin-3-yl]methylamine

A mixture of 50 mmol of3-(4-methoxyphenyl)-3-methyl-5-[1-nitrometh-(Z)-ylidene]morpholine and 5teaspoons full of Raney nickel in 500 ml of tetrahydrofuran and 250 mlof methanol is hydrogenated under atmospheric pressure for 5 hours. Thereaction mixture is filtered through Hyflo and the filtrate isevaporated. The crude title compound is identified from the residue onthe basis of the Rf. The title compound is employed without furtherpurification in the next stage.

f1) 3-(4-Methoxyphenyl)-3-methyl-5-[1-nitrometh-(Z)-ylidene]morpholine

A mixture of 100 mmol of[5-(4-methoxyphenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-N-nitroso-N-methylamine,200 ml of N,N-dimethylformamide, 50 ml of nitromethane and 115 mmol ofpotassium tert-butoxide is stirred at room temperature for 15 minutes.It is quenched by adding 20 ml of glacial acetic acid and diluted withdichloromethane and water. The organic phase is separated off, washedwith water, dried with sodium sulphate and evaporated. The titlecompound is identified from the residue on the basis of the Rf by flashchromatography (SiO₂ 60F).

g)[5-(4-Methoxyphenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-N-nitroso-N-methylamine

125 mmol of sodium nitrite are added in portions to a solution of 100mmol of[5-(4-methoxy-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]methylaminein 200 ml of glacial acetic acid at room temperature. The reactionmixture is stirred for 1.5 hours. It is diluted with dichloro-methaneand water. The organic phase is separated off, washed with water, driedwith sodium sulphate and evaporated. The title compound is identifiedfrom the residue on the basis of the Rf by flash chromatography.

h)[5-(4-Methoxyphenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]methylamine

A solution of 69.5 mmol of 5-(4-methoxyphenyl)-5-methylmorpholin-3-onein 200 ml of tetrahydrofuran and 25 ml of benzene is cooled to 0° C. andsaturated with methylamine. A solution of 19 g of titanium tetrachloridein 25 ml of benzene is added dropwise over the course of 15 minutes.After addition is complete, the reaction mixture is heated to reflux for3 hours. The reaction mixture is then cooled to 0° C. and cautiouslyquenched with 60 ml of water. It is filtered through Hyflo, and thefilter cake is washed several times with tetrahydro-furan. The phases ofthe filtrate are separated, and the organic phase is dried with sodiumsulphate and evaporated. The title compound is identified from theresidue oh the basis of the Rf by flash chromatography (SiO₂ 60F).

i) 5-(4-Methoxyphenyl)-5-methylmorpholin-3-one

A solution of 129.1 mmol of potassium tert-butoxide in 100 ml oftert-amyl alcohol is mixed at room temperature with 51.6 mmol of2-chloro-N-[2-hydroxy-1-(4-methoxyphenyl)-1-methyl-ethyl]acetamide andstirred for 3 hours. The reaction mixture is diluted with 50 ml ofmethanol and 3 ml of water and evaporated. The title compound isobtained as a white solid from the residue by flash chromatography (SiO₂60F). Rf=0.10 (ethyl acetate-heptane 2:1), Rt=2.81 (gradient I).

j), 2-Chloro-N-[2-hydroxy-1-(4-methoxyphenyl)-1-methylethyl]acetamide

A solution of 57.5 mmol of 2-amino-2-(4-methoxyphenyl)propan-1-ol in 190ml of acetonitrile and 33 ml of methanol is cooled to −10° C., and 69mmol of triethylamine and, dropwise over the course of 1 hour, 63.3 mmolof chloroacetyl chloride are successively added. The reaction mixture iswarmed to room temperature and stirred for 16 hours. The mixture isevaporated, and the title compound is obtained as a colourless oil fromthe residue by flash chromatography (SiO₂ 60F). Rf=0.23 (ethylacetate-heptane 2:1), Rt=2.88 (gradient I).

k) 2-Amino-2-(4-methoxyphenyl)propan-1-ol

A solution of 15.0 mmol of 2-amino-2-(4-methoxyphenyl)propionic acid[74279-63-3] in 15 ml of tetrahydrofuran is added dropwise to asuspension of 30.0 mmol of lithium aluminium hydride in 5 ml oftetrahydrofuran. The reaction mixture is heated to reflux for 1 hour. Itis quenched with a little water and 1M NaOH and stilted at roomtemperature. The suspension is filtered through Hyflo. The filtrate isevaporated. The title compound is obtained as a pale yellowish oil,which may crystallize, and is employed without further purification inthe next stage. Rt=1.97 (gradient I).

Alternative syntheses forC-[5-(4-methoxyphenyl)-5-methylmorpholin-3-yl]methylamine

e2) C-[5-(4-Methoxyphenyl)-5-methylmoroholin-3-yl]-methylamine

A mixture of 40.1 mmol of5-(4-methoxyphenyl)-5-methylmorpholine-3-carbonitrile and 2 g of Raneynickel (activated by washing with water to pH 7 and subsequent washingwith ethanol) in 200 ml of ethanol is hydrogenated under a pressure of500 psi for 12 hours. The reaction mixture is filtered through Hyflo andthe filtrate is evaporated. The crude title compound is identified fromthe residue on the basis of the Rf. The title compound is employedwithout further purification in the next stage.

f2) 5-(4-Methoxyphenyl)-5-methylmorpholine-3-carbonitrile

A solution of 160 mmol of lithium aluminium hydride (1M in hexane) in750 ml of tetrahydro-furan is mixed at 0° C. with 7.8 ml of ethylacetate and stirred at 0° C. for 2 hours. A solution of 20 mmol of5-(4-methoxyphenyl)-5-methylmorpholin-3-one (Example 3i) in 250 ml oftetrahydrofuran is added dropwise to this solution, and the reactionmixture is stirred at 0° C. for 45 minutes. 600 ml of glacial aceticacid and then 120 mmol of a 4.5M aqueous potassium cyanide solution areadded. The mixture is stirred at room temperature for 16 hours. Thereaction mixture is diluted with 1M sodium bicarbonate solution andextracted with ethyl acetate-tetrahydrofuran 1:1 (3×). The combinedorganic phases are washed with brine, dried with sodium sulphate andevaporated. The title compound is obtained as a pale yellowish oil fromthe residue by flash chromatography (SiO₂ 60F). Rf=0.19 (CH₂Cl2-MeOH95:5); Rt=2.41 (gradient I).

e3) C-[5-(4-Methoxyphenyl)-5-methylmorpholin-3-yl]methylamine

A solution of 2.25 mmol of5-(4-methoxyphenyl)-5-methylmorpholin-3-carbonitrile (Example 3f2) in 10ml of tetrahydrofuran is cooled to 0-5° C. in an ice bath. 6.75 mmol oflithium aluminium hydride are added in portions, and the reactionmixture is then stirred at room temperature for 1 hour. The reactionmixture is quenched with 0.5 ml of methanol and mixed with 40 ml ofdichloromethane and 0.060 g of solid potassium carbonate, and 0.60 ml ofwater. The suspension is filtered through Hyflo and the filter cake iswashed with dichloromethane. The filtrate is evaporated. The titlecompound is obtained as a colourless oil from the residue by flashchromatography (SiO₂ 60F). Rf=0.26 (dichloromethane-methanol-25% aqueousammonia solution 200:20:1), Rt=2.13 (gradient I)

The following compounds are prepared in analogy to the process describedin Example 3:

44-(5-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]thiazin-5-yl)benzonitrile

starting from 2-amino-2-(4-methoxyphenyl)propane-1-thiol

The starting material is prepared as follows:

a) 2-Amino-2-(4-methoxyphenyl)propane-1-thiol

A solution of 1 mmol of 2-amino-2-(4-methoxyphenyl)propan-1-ol (Example3k) and 0.5 mmol of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane2,4-disulfide (Lawesson's reagent) [19172-47-5] in 10 ml of toluene isheated to reflux for 2 hours. The reaction mixture is cooled to roomtemperature and evaporated. The title compound is identified from theresidue on the basis of the Rf by flash chromatography (SiO₂ 60F).

5 4-(5-Ethyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)benzonitrile

starting from 4-(1-amino-1-hydroxymethylpropyl)benzonitrile[756440-42-3].

Example 85-[4-(1H-Tetrazol-5-yl)phenyl]-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine

A solution of 0.17 mmol of4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)benzonitrile(Example 1) and 0.017 nimbi of dibutyltin oxide in 4.6 ml of toluene ismixed with 3.34 mmol of trimethylsilyl azide. The reaction mixture isheated at 125° C. overnight. It is cooled to room temperature andevaporated. The title compound is identified from the residue on thebasis of the Rf by flash chromatography (SiO₂ 60F).

16 1-[4-5,6-Dihydro-8H-imidazo[5,1-c][1.4]oxazin-5-yl)phenyl]ethanone

0.47 mmol of methylmagnesium bromide solution (3M in diethyl ether) isadded to a suspension of 0.47 mmol of4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)benzonitrile(Example 1) in 5 ml of absolute toluene. The reaction mixture is heatedto reflux for 16 hours, cooled and mixed with dilute aqueous sodiumbicarbonate solution. The mixture is extracted with ethylacetate-dichloromethane 4:1, and the combined organic phases are washedwith brine, dried with sodium sulphate and evaporated. The titlecompound is obtained as a slightly whitish solid from the residue byflash chromatography (SiO₂ 60F). Rf=0.34 (dichloromethane-methanol95:5); Rt=3.54 (gradient II).

Example 18 4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)benzonitrile

The racemic compound4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)benzonitrile(Example 1) is fractionated into the enantiomers by chiral preparativeHPLC. The title compound is isolated as the enantiomer which elutessecond. Rt*=11.39 min.

*HPLC method:

Column: 250×50 mm CHIRALPAK® AD 20 μm

Mobile phase: CO₂/methanol 80:20Flow rate: 240 ml/min

Detection: UV 250 nm Temperature: 25° C.

Pressure: 150 bar

1-12. (canceled)
 13. A compound of the general formula

in which R is deuterium, halogen or hydrogen; R¹ is aryl-C₀-C₄-alkyl orheterocyclyl-C₀-C₄-alkyl, which radicals are unsubstituted orsubstituted by 1-4 C₁-C₈ alkoxy, C₁-C₈ alkoxycarbonyl, C₁-C₈ alkyl,C₀-C₈ alkylcarbonyl, C₁-C₈ alkylsulphonyl, optionally substituted aryl,aryl-C₀-C₄ alkoxycarbonyl, cyano, halogen, optionally substitutedheterocyclyl, hydroxy, nitro, oxide, oxo, tri-C₁-C₄-alkylsilyl,trifluoromethoxy or trifluoromethyl; R² is a) deuterium, halogen,hydroxy, cyano or hydrogen; or b) C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈alkoxy, C₁-C₄ alkoxycarbonyl-C₁-C₄ alkyl, C₁-C₈ alkyl, C₀-C₄alkylcarbonyl, aryl-C₀-C₄ alkyl, carboxy-C₁-C₄ alkyl, C₃-C₈ cycloalkylor heterocyclyl-C₀-C₄ alkyl, which radicals are unsubstituted orsubstituted by 1-4 C₁-C₈ alkoxy, C₁-C₈ alkoxycarbonyl, C₁-C₈ alkyl,C₀-C₈ alkylcarbonyl, C₁-C₈ alkylsulphonyl, optionally substituted aryl,aryl-C₀-C₄ alkoxycarbonyl, cyano, halogen, optionally substitutedheterocyclyl, hydroxy, nitro, oxide, oxo, tri-C₁-C₄ alkylsilyl,trifluoromethoxy or trifluoromethyl; Q is oxygen or sulphur; m is anumber 0, 1 or 2; n is a number 0, 1 or 2; where m and n are notsimultaneously 0; and a salt, preferably a pharmaceutically acceptablesalt, thereof.
 14. A compound according to claim 13, which correspondsto the general formula

where the meanings of the substituents R, R¹, R², Q, m and n are asindicated for compounds of the formula (I) according to Claim 13, and *designates an asymmetric carbon atom and which compound shows analdosterone synthase and/or 11-β-hydroxylase inhibitory activity atleast 10 times higher, but preferably 20 times higher, or morepreferably 40 times higher, than the compound of the formula (Ia) withthe opposite configuration around the asymmetric carbon atom labelled“*”.
 15. A compound according to claim 13, where R is deuterium orhydrogen.
 16. A compound according to claim 13, where R¹ is optionallymono-, di- or tri-substituted phenyl or optionally mono-, di- ortri-substituted benzofuranyl, benzo[b]thiophenyl, benzoimidazolyl,benzo[d]isothiazolyl, benzo[d]isoxazolyl, benzo[b]thiophenyl,imidazolyl, indazolyl, oxazolyl, pyridyl, pyrrolyl, thiazolyl orthiophenyl.
 17. A compound according to claim 13, where R is C₁-C₈alkoxy, hydroxy, C₁-C₈ alkyl, aryl-C₀-C₄ alkyl, deuterium, halogen,cyano or hydrogen.
 18. A method for the prevention, for delaying theprogression or for the treatment of pathological states which are causedor partly caused by hyperaldosteronism, where a therapeuticallyeffective amount of a compound of the general formula (I) or apharmaceutically acceptable salt thereof according to claim 13 is used.19. A method for the prevention, for delaying the progression or for thetreatment of pathological states which are caused or partly caused byhyperaldosteronism, where a therapeutically effective amount of acompound of the general formula (Ia) or a pharmaceutically acceptablesalt thereof according to claim 14 is used.
 20. A method for theprevention, for delaying the progression or for the treatment ofpathological states which are caused or partly caused by excessiveCortisol release, where a therapeutically effective amount of a compoundof the general formula (I) or a pharmaceutically acceptable salt thereofaccording to claim 13 is used.
 21. A method for the prevention, fordelaying the progression or for the treatment of pathological stateswhich are caused or partly caused by excessive Cortisol release, where atherapeutically effective amount of a compound of the general formula(Ia) or a pharmaceutically acceptable salt thereof according to claim 14is used.
 22. A pharmaceutical composition comprising a compound of thegeneral formula (I) or a pharmaceutically acceptable salt thereofaccording to claim 13, and conventional excipients.
 23. A pharmaceuticalcomposition comprising a compound of the general formula (Ia) or apharmaceutically acceptable salt thereof according to claim 14, andconventional excipients.
 24. A pharmaceutical composition in the form ofa product or of a kit composed of individual components consisting a) ofa compound of the general formula (I) or a pharmaceutically acceptablesalt thereof according to claim 13, and b) at least one pharmaceuticalform whose active ingredient has a blood pressure-lowering, aninotropic, a metabolic or a lipid-lowering effect.
 25. A pharmaceuticalcomposition in the form of a product or of a kit composed of individualcomponents consisting a) of a compound of the general formula (Ia) or apharmaceutically acceptable salt thereof according to claim 14, and b)at least one pharmaceutical form whose active ingredient has a bloodpressure-lowering, an inotropic, a metabolic or a lipid-lowering effect.